The present invention is directed to novel derivatives of 2-phenyl-1,3-propanediol dicarbamate (felbamate), and the use of such derivatives as therapeutic agents. More particularly, compositions comprising the present felbamate derivatives can be administered for reducing the incidence and severity of epileptic seizures and for preventing and treating hypoxic damage resulting from an ischemic event.
Felbamate (2-phenyl-1,3-propanediol dicarbamate) is a known pharmaceutical compound having been described in U.S. Pat. Nos. 2,884,444 and 4,868,327, the disclosures of which are expressly incorporated herein. Felbamate is a modulator of NMDA (N-methyl-D-aspartate) receptor function, and a glycine site antagonist but also has other reported mechanisms of actions.
Felbamate has also been reported to interact at the AMPA/kainate receptor, facilitate the function of the GABA receptor, and modulate Na.sup.+ channel conductance. Felbamate has also been demonstrated to decrease delayed neuronal cell death after kainic acid induced status epilepticus in animals. Glycine or d-serine were able to functionally reverse the anticonvulsant and ischemic protective effect of felbamate.
Felbamate has been proposed for use in treating various neurological disorders including the control of epileptic seizures. For example, U.S. Pat. No. 4,978,680 discloses the use of felbamate for the prevention and control of epileptic seizures; U.S. Pat. No. 5,082,861 relates to the use of felbamate for the prevention and control of epileptic seizures associated with complex partial seizures; and U.S. Pat. No. 5,292,772 relates to the use of felbamate for the prevention and control of epileptic seizures associated with Lennox-Gastaut syndrome. The disclosures of U.S. Pat. Nos. 4,978,680, 5,082,861 and 5,292,772 are expressly incorporated herein.
Felbamate has also been reported to have efficacy in reducing cellular damage resulting from vascular reperfusion (U.S. Pat. No. 5,462,966) and preventing and treating tissue damage resulting from an ischemic event (U.S. Pat. No. 5,055,489). For example, compositions comprising felbamate can be administered to control or prevent hypoxic damage resulting form stroke and other cerebral ischemic events. The disclosure of U.S. Pat. Nos. 5,462,966 and 5,055,489 are also expressly incorporated herein.
Felbamate was approved in July 1993 for the treatment of several forms of epilepsy. Felbamate demonstrated an excellent therapeutic index throughout preclinical and clinical trials with only relatively mild side effects observed and/or reported. In its first year of approval, between 100,000 and 125,000 patients were placed on felbamate therapy in the U.S. However, within the first year of felbamate""s wide spread use, adverse reactions were reported, notably aplastic anemia and hepatotoxicity. (See Pennell et al., Neurology. 45, 456-460 (1995) and O""Neil et al., Neurology. 46, 1457-1459 (1996)). The severity and frequency of occurrence of these side effects prompted a recommendation by the FDA in August 1994 to withdraw patients from felbamate therapy, unless the benefit of seizure control outweighed the risk of the reported toxicities.
The present invention is directed to felbamate derivatives, and their metabolites, that exhibit therapeutic properties similar to felbamate, without the adverse reactions observed with felbamate administration. In accordance with the present invention these felbamate derivatives are used to treat neurological disorders and prevent and/or control tissue damage resulting from hypoxic conditions. More particularly, the present novel compounds are believed to be useful for treating epileptic seizures and for preventing or alleviating cellular damaged caused by myocardial or cerebral ischemic events.
The presently disclosed derivatives of felbamate have been shown to have activity as neuroprotectants and are believed to have biological activities similar to those of the parent felbamate compound. However, the present compounds have been modified to prevent the formation of metabolites that are believed to cause the adverse reactions associated with the use of felbamate. Accordingly, it is anticipated that the felbamate derivatives of the present invention can be substituted for felbamate for all the therapeutic uses that have been proposed for felbamate. In addition, many of the derivatives have enhanced activities allowing for the administration of lower therapeutically effective dosage forms.
The present invention is directed to novel compounds of the general formula: 
wherein X is selected from the group consisting of 
and R1, R7, R8, R9 and R10 are independently selected from the group consisting of H, halo, alkyl, haloalkyl, xe2x80x94NR5R6, hydroxy, and alkoxy, R2 is halo, R3 is hydroxy or xe2x80x94OCONH2, R4 is hydroxy or carbonyl, and R5 and R6 are independently C1-C4 alkyl. These novel compounds are derivatives of febamate; and in particular, the original felbamate structure has been modified to prevent the formation of metabolite 2-phenylpropenyl (atropaldehyde) upon administration to a warm blooded vertebrate. The formation of atropaldehyde is believed to be responsible for the adverse effects associated with the administration of felbamate. These felbamate derivatives exhibit similar activities to felbamate without the risk of the toxicities associated with felbamate administration. In accordance with the present invention compositions comprising a felbamate derivative are administered to a patient to provide neuroprotection in systemic and neurological disease and to treat tissue damage resulting from ischemic events. The compounds can be administered prophylactically, acutely, subacutely, or chronically via the intravenous, oral or rectal route.
In describing and claiming the invention, the following terminology will be used in accordance with the definitions set forth below.
As used herein, the term xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d encompasses any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water and emulsions such as an oil/water or water/oil emulsion, and various types of wetting agents.
As used herein, xe2x80x9ceffective amountxe2x80x9d means an amount sufficient to produce a selected effect. For example, an effective amount of a neuroprotective felbamate derivative is an amount of the active agent sufficient to significantly reduce the incidence and severity of epileptic seizures. An effective amount of a hypoxia ameliorating felbamate derivative is an amount of the active agent sufficient to prevent or significantly reduce cellular damage resulting from coronary artery occlusion/reperfusion or other hypoxia inducing event.
The general chemical terms used in the description of the compounds of the present invention have their usual meanings. For example, the term xe2x80x9calkylxe2x80x9d by itself or as part of another substituent means a straight or branched aliphatic chain having the stated number of carbon atoms.
The term xe2x80x9chaloxe2x80x9d includes bromo, chloro, fluoro, and iodo.
The term, xe2x80x9cparenteralxe2x80x9d means not through the alimentary canal but by some other route such as subcutaneous, intramuscular, intraspinal, or intravenous.
As used herein, the term xe2x80x9ctreatingxe2x80x9d includes alleviating the symptoms associated with a specific disorder or condition and/or preventing or eliminating said symptoms.
The following metabolic pathway (Scheme I) of felbamate (1) has been proposed that leads to the reactive metabolite, 3-carbamoyl-2-phenylpropionaldehyde (3). 
3-Carbamoyl-2-phenylpropionaldehyde (3) is believed to be a reactive intermediate in the oxidation of 2-phenyl-1,3-propanediol monocarbamate (2) to the major human metabolite 3-carbamoyl-2-phenylpropionic acid (4). In addition, the aldehyde carbamate (3) was found to undergo spontaneous elimination to form the xcex1,xcex2 unsaturated aldehyde, 2-phenylpropenal (5), commonly known as atropaldehyde. Atropaldehyde has been proposed to play a role in the development of toxicity during felbamate therapy.
Evidence for atropaldehyde formation in vivo has been reported with the identification of modified N-acetyl-cysteine conjugates 7 and 8 of atropaldehyde in both human and rat urine after felbamate administration. Identification of the atropaldehyde derived mercapturic acids in urine after felbamate administration is consistent with the hypothesis that atropaldehyde is formed in vivo and that it reacts with thiol nucleophiles.
Based on the hypothesis that the toxicity associated with felbamate administration is directly correlated to the amount of atropaldehyde formed, the present invention is directed to the development of a new class of agents structurally related to felbamate that cannot undergo metabolism to atropaldehyde.
In accordance with the present invention the benzylic hydrogen of felbamate (1) is replaced with a substituent xe2x80x9cR2xe2x80x9d as shown in the following metabolic scheme (Scheme II). R2 is halo, and in one preferred embodiment the substituent is a fluorine atom. 
Fluorofelbamate (12) and fluoro monocarbamate felbamate (13) are derivatives of known antiepileptic agents. These agents represent a new class of anti-epileptics that, while possessing structural similarity to felbamate, will not exhibit felbamate""s metabolic profile and will not induce adverse reactions such as those associated with the use of felbamate.
In accordance with one embodiment of the present invention these compounds can be further modified to include substituents at the para position of the benzene ring of the felbamate derivative to preclude the formation of other potentially toxic species via the cytochrome P450 pathway. This potential cytochrome P450 mediated toxicity may be associated with the 2-substituted-2-phenyl-1,3-propanediol-dicarbamate derivatives of the present invention by formation of electrophilic species such as 19, which may also be formed from dihydroxy felbmate, a known metabolite of felbamate. Febamate derivative compounds that are substituted at the para position are blocked from being metabolized by certain members of the cytochrome P450 metabolic family. For example, two preferred compounds are diflurofelbamate (23) and difluoro monocarbamate felbamate (24). These febamate derivatives are incapable of being metabolized to atropaldehyde and also are blocked from being metabolized by certain members of the cytochrome P450 metabolic family. 
The present invention also encompasses the derivatives of the potentially active metabolites of felbamate. In particular this includes fluoro oxazinane-dione 16 and difluoro oxazinane-dione, which are derivatives of the felbamate metabolite oxazinane-dione 9. The structure of oxazinane-dione 9 bears intriguing similarity to several established anti-epileptic drugs including phenobarbital, phenytoin, oxazinane-dione, metharbital and ethotoin, as illustrated below: 
It is anticipated, therefore, that the oxazinane-dione 9 is responsible for some aspects of felbamate""s efficacy in vivo. As patients undergoing felbamate therapy for seizure control ingest large quantities of felbamate (grams per day), even a 1-2% conversion to a pharmacologically active metabolite could have significant effects. This could play an important role in the seizure control observed with felbamate, particularly if the metabolite (i.e., the oxazinane-dione) was a more potent compound. In light of the possibility that the oxazinane-dione 9 could be a metabolic precursor to the major human metabolite, acid carbamate 4, it may be formed in significant quantities (the acid carbamate was reported to represent xcx9c12% of a dose). Because the parent oxazinane-dione 9 has been found to be unstable at relevant pH, oxazinane-diones 16 are considered candidates for development as potential antiepileptic agents. Also included in this class are cyclic congeners 21 and 22, which may be formed from felbamate derivatives (see scheme II). Also included is 20, which may be an unknown metabolite of felbamate 1 and could be produced from felbamate derivative 12 by the cytochrome P450 metabolism.
In accordance with one embodiment of the present invention a neurological disorder or localized ischemic event (myocardial or cerebral ischemia) is treated by administering a compound having the general structure: 
wherein X is selected from the group consisting of 
and R1, and R7 are independently selected from the group consisting of H, halo, alkyl, haloalkyl, xe2x80x94NR5R6, hydroxy, and alkoxy, R2 is Cl or F, R3 is hydroxy or xe2x80x94OCONH2, R4 is hydroxy or carbonyl, R5 and R6 are independently C1-C4 alkyl.
In an alternative embodiment a neurological disorder or localized ischemic event (myocardial or cerebral ischemia) is treated by administering a compound having the general structure: 
wherein X is selected from the group consisting of 
and R1, and R8 are independently selected from the group consisting of H, halo, alkyl, haloalkyl, xe2x80x94NR5R6, hydroxy, and alkoxy, R2 is Cl or F, R3 is hydroxy or xe2x80x94OCONH2, R4 is hydroxy or carbonyl, R5 and R6 are independently C1-C4 alkyl, is administered to a patient to treat a neurological disorder or myocardial or cerebral ischemia.
In accordance with one embodiment, the compound is selected from the group consisting of 
wherein R1 is selected from the group consisting of H, halo, alkyl, haloalkyl, xe2x80x94NR5R6, hydroxy, and alkoxy, R3 is hydroxy or xe2x80x94OCONH2, R4 is hydroxy or carbonyl, and R5 and R6 are independently C1-C4 alkyl, is administered to a patient to treat a neurological disorder or myocardial or cerebral ischemia.
In accordance with another embodiment the compound is selected from the group consisting of 
wherein R1 is selected from the group consisting of H or halo, R3 is hydroxy or xe2x80x94OCONH2, and R4 is hydroxy or carbonyl, and in one preferred embodiment the compound is selected from the group consisting of 
wherein R1 is selected from the group consisting of H, F, Cl, CF3 and hydroxy and R3 is hydroxy or xe2x80x94OCONH2. In one preferred embodiment R1 is H or F and R3 is xe2x80x94OCONH2.
Compositions comprising the felbamate derivative of the present invention can be used to treat patients suffering from a neurological diseases such as epileptic seizures or can be used to prevent or treat reperfusion injuries resulting from stroke, myocardial infarction, and spinal chord perfusion-type injuries. It is believed that the felbamate derivatives of the present invention also have utility for treating conditions characterized by the presence of reactive oxygen species (ROS).
The felbamate derivative of the present invention can be combined with pharmaceutically acceptable carriers, stabilizing agents, solubilizing agents, and fillers known to those skilled in the art for administration to the patient. The compositions can be formulated using standard delivery vehicles and standard formulations for oral, parenteral or transdermal delivery.
In accordance with one embodiment a patient suffering from a neurological disorder or from a reperfusion injury can be treated with the felbamate derivatives, and/or the metabolites of the felbamate derivatives to alleviate the symtoms associated with said disorder or injury. In accordance with the present invention a method for treating patients suffering from a neurological diseases such as epileptic seizures or for treating reperfusion injuries comprises the steps of administering to the patient a composition comprising a compound is selected from the group consisting of 
wherein R1 is selected from the group consisting of H, halo, alkyl, haloalkyl and hydroxy, R3 is hydroxy or xe2x80x94OCONH2, and R4 is hydroxy or carbonyl, in combination with a pharmaceutically acceptable carrier. In one preferred embodiment the composition comprises a compound selected from the group consisting of 
wherein R1 is selected from the group consisting of H, F, Cl, CF3 and hydroxy, R3 is hydroxy or xe2x80x94OCONH2 in combination with a pharmaceutically acceptable carrier.
When administered orally, the compounds can be administered as a liquid solution, powder, tablet, capsule or lozenge. The compounds can be used in combination with one or more conventional pharmaceutical additive or excipients used in the preparation of tablets, capsules, lozenges and other orally administrable forms. When administered as an intravenous solution, the derivatives of the present invention can be admixed with conventional IV solutions.
The compounds of the present invention are administered at a dose range effective to alleviate the symptoms associated with the disorder. In accordance with one embodiment the felbamate derivative (active agent) is administered in a dosage form of about 0.1 mg/kg to about 5.0 g/kg, and more particularly about 0.25 mg/kg to about 1 g/kg. The dosage will vary based on the route of administration and the condition/disorder to be treated.